Nucleophilic Addition of 4,5-Dihydrooxazole Derivatives to Base Generated o-Quinone Methides: A Four-Component Reaction

A novel method for joining four components together in a single pot leading to an assortment of N-amino-benzylated phenols is described. The method involves the addition of different Grignard reagents to various o-OBoc salicylaldehydes in the presence of assorted 4,5-dihydrooxazoles, followed by aqueous workup. Seventeen examples are presented with varied (-R, -R′ -R″, -R‴, -R⁗, and Cn) substituents.


W e recently described a synthetic method involving ortho-
quinone methides (o-QMs), which are base generated by the addition of assorted Grignard reagents to various ortho-OBoc salicylaldehydes and observed to undergo reaction with the sp 2 nitrogen atom of various imine nucleophiles and afford the corresponding 3,4-dihydro-2H-1,3-benzoxazines in good yields and diastereoselectivities (Scheme 1: i). 1 As a multi three-component reaction (M3CR) 2 comprised of a salicylaldehyde, a Grignard reagent, and an imine, this earlier process enables the rapid exploration of benzylic amine substrate space. 3 Herein, we report an unexpected M4CR from replacement of the imine with dihydro-4,5-oxazole derivatives followed by hydrolytic workup of a zwitterionic intermediate.
Originally, we had postulated that introduction of 4,5dihydrooxazoles should deliver the corresponding tricyclic 1,3benzoxazine adduct as opposed to the earlier bicyclic adducts observed for imines (Scheme 1: ii). 1 When this result failed to transpire, we paused to consider the inherent reactivity of 4,5dihydrooxazoles with electrophilic reagents (Scheme 2). We found the literature bursting with examples of cationic ring opening polymerization, and reports of block copolymer formation leading to polyamides via a pseudo-living oxazolinum terminus thermodynamically driven toward amide formation (Scheme 2: i). 4 These were instigated by the addition of a small amount of an electrophilic initiator, which included an assortment of Brønsted or Lewis acids, as well as alkylation or acylation reagents under neat conditions. These reactions afforded poly-N-acylethylenimines of tunable molecular weight that were bioisosteric with polypeptides. In addition, several nonpolymerizing ring openings of dihydrooxazole have been noted at reduced temperatures. These required that the electrophile and nucleophile be introduced at a near parity of equivalents under dilute conditions. For example, after Lewis acid activation, aryl nucleophiles had been observed to add at the 5-position of the oxazolium intermediates in a diastereoselective fashion (Scheme 2: ii). 5 Other ring openings included protonation with an acid displaying a weakly nucleophilic counteranion followed by the addition of a secondary amine (Scheme 2: iii). 6 Upon application of ethyl chloroformate, on the other hand, the chloride anion was found to open the oxazolium ring (Scheme 2: iv). 7 In addition, there was a solitary report of "wet" lowtemperature conditions, whereby opportunistic water intercepted the cationic species to provide an ammonium intermediate that underwent regioselective ring opening and amine expulsion to produce an ester and ammonium species (Scheme 2: v) 8 with regioselective ring opening attributed to stereoelectronic control. 9 We were therefore keen to determine if any related products had arisen from our low temperature in situ generation of electrophilic o-QMs in the presence of various 4,5-dihydrooxazoles. Our analyses showed that products 25−41 (Table 1) had emerged from our usual conditions; addition of the Grignard reagent to the aldehyde 0.1 M in diethyl ether at −78°C , followed by addition of the 4,5-dihydrooxazole (2 equiv) and slowly warming to RT over 24 h, followed by an aqueous workup with 1 M NaHCO 3. Upon close inspection of the respective 1 H NMR spectra, we noted that the benzylic methine resonances displayed a signal of about 4.0 ppm, whereas the corresponding benzylic amide methines generally arise at about 5.0 ppm. Thus, the 1 H NMR spectra and the lack of rotamers revealed that the reaction had followed pathway v in Scheme 2, whereby opportunistic water had intercepted the oxazolium intermediate upon workup as the fourth component of a new M4CR.
Fruitful combinations of salicylic aldehydes, Grignard reagents, and dihydrooxazoles, followed by aqueous bicarbonate are shown in Figure 1. The trend among yields for the aromatic cores 1−4 ( Table 1, entries 1−5) reflected of our earlier observations in which similar o-QMs have been generated and intercepted by either organometallic species, 10 alkenes, 11 imines, 1 or other carbon nucleophiles. 12 Salicylaldehydes displaying electron donating substituents (C2−C4) usually provide stable o-QM species leading to better controlled reactions, 13 whereas the o-QM derived from compound 1 (-R = -H) (entry 4, Table 1) without donating substituents resulted in moderate self-destruction and lower overall yields (entry 4, 49%). 14 Grignard reagents 6−9 containing bromide ( Remarkably, the furyl oxazole derivative 15 proved successful (Table 1, entry 15, 29% yield), whereas the dihydrooxazole analogues 18 and 19 ( Figure 2) did not. Given that oxazole 20 also failed to provide significant product, we attribute their collective shortcomings to a combination of steric encumbrances interfering with nitrogen atom nucleophilicity, as well as an enhanced oxazolium stability and lower reactivity of the respective intermediates. These traits thwart either the initial addition of the nitrogen nucleophile, or the subsequent addition of water. We ascribed unsuccessful reactions of compounds 21−24 to proton acidities within their relevant oxazolium intermediates resulting in a propensity toward substrate deprotonation and destruction.
Compound 25 was observed to undergo several useful and illuminative transformations. For example, its ester moiety undergoes saponification with potassium carbonate in On the other hand, upon heating compound 25 to 90°C in acetonitrile in the presence of imidazole (1 equiv), we observed formation of compound 44 (55%) along with styrene (<25%). The styrene likely arises from a proton transfer from within the imidazolium zwitterionic formed after imidazole addition to the o-QM. Figure 3 shows our postulated mechanism and explains formation of the compounds in both Table 1 and Scheme 3.
We find aldehyde 3a and methyl Grignard 5 undergo reaction at −78°C (0.1 M in Et 2 O) to provide the speculative cyclic intermediate A. This alkoxide species can collapse three possible ways. It collapses to afford the more stable phenoxide B, as opposed to the two other plausible albeit less stable alkoxides. Next, at some temperature between −60 to −20°C (both R and R′ substituent dependent), the phenoxide expels the less basic tert-butyl carbonate sequestered as a magnesium salt to form the highly reactive o-QM C. Remarkably, lithium salts do not appear to undergo the β-elimination from B to C. 10a,15 At these temperatures o-QMs with a β-methyl, as opposed to β-phenyl systems, undergo rapid self-destruction in the absence of a nucleophilic partner. However, in the presence of the dihydrooxazole, we surmise that it engages the o-QM around −20°C to form the dihydrooxazolium zwitterion D, which appears more stable than intermediate B. , we postulate that the ester moiety undergoes rearrangement to the corresponding amide G, which undergoes immediate and irreversible elimination of the amide alcohol to provide the E-o-QM C.
To strengthen these mechanistic hypotheses, we carried out the experiments shown in Scheme 4. First, we deployed our traditional low temperature cycloaddition protocol with ethoxyvinyl ether (EVE), 10 which afforded the benzopyran 45a as single diastereomer. This outcome supports the notion that at these low temperatures the o-QM E-C is not in equilibrium with the o-QM Z-C, because no styrene is observed, and endo diastereoselectivity for the benzopyran 45a is outstanding. Remarkably, our attempts toward orchestrating a crossover or disrupting stereochemistry by heating 45a (>120°C) for 2 days failed. Thus, we concluded that 45a is not an o-QM precursor at 120°C. Next, we replaced

. Experiments with o-QM Precursors
The Journal of Organic Chemistry pubs.acs.org/joc Note EVE with dihydrooxazole 10 and carried out the same process resulting in the speculative zwitterion D, whereupon we introduced EVE. No formation of benzopyran 45 was apparent over the course of 24 h at RT. However, upon heating to 60°C we isolated the benzopyran 45b in a 1.6:1 diastereomeric ratio along with the dihydrooxazole 10. Thus, we speculate that around 60°C the zwitterion D undergoes elimination to return the o-QM E-C and either undergoes reaction in both endo and exo manifolds, or it exists in an equilibrium alongside the o-QM Z-C′ which undergoes reaction in an endo format. However, the absences of styrene 43 supports the former notion. Lastly, we heated the amine 25 in the presence of EVE at 60°C in a sealed tube for 2 days and observed no reaction. Thus, we surmise from the experiment that the order of stability among these o-QM precursors is 45a > 25 > 44 > D > B, with all being R and R′ dependent.
Several natural products and their derivatives can be imagined as amenable to synthesis using this novel M(4)CR method ( Figure 4). (±)-Stritida B and C (51a,b) are the first pyridocarbazole alkaloids reported to display an N-2hydroxyethyl residue. 16 (+)-Hispidacine (52), an 8,4′-oxyneolignan alkaloid displaying vasorelaxant activity, also manifests this motif. 17 (±)-Irpexine (53), an isoindolinone alkaloid, exhibits this substituent as well. 18 However, we chose to explore the application of this M(4)CR toward the synthesis of mariline B (54), a naturally occurring racemic phthalimidine isolated from the sponge derived fungus Stachylidium sp. 19 Construction of the isoindolinone from adduct 29 necessitated a carbonylation to replace the phenol residue and connect it with the neighboring benzylic amine. This first required conditions for selective phenol triflation in the presence of a free amine (Scheme 6). This was modestly accomplished using biphasic conditions developed by Sonesson, and it provided a sufficient yield of the corresponding triflate 55 to test our strategy. 20 Using a modified palladium carbonylation chemistry developed by Crisp, 21 we observed the phthalimidine to smoothly form upon exposure to carbon monoxide and palladium with the appropriate catalyst. Further in situ saponification afforded the desired phthalimidine 56 in 61% yield.
In conclusion, a M4CR has been developed that enables various combinations of ortho-OBoc salicylaldehydes, Grignards, dihydrooxazoles, and water. The method provides a large array of structurally diverse products possessing a masked N-2-hydroxyethyl residue. This transformation involves an unusual zwitterionic dihydrooxazole o-QM precursor that proves stable at RT. This unexpected species leads to the corresponding benzopyran [4 + 2] adducts without diastereoselectivity. In addition, this zwitterionic intermediate undergoes regioselective opportunistic addition of water. Moreover, we anticipate this species D can be selectively intercepted by other nucleophiles at either its 2-or 5positions. 22 Progress in this endeavor will be reported in due course.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Representative experimental procedures; Characterization data for all new compounds including 1 H, 13 C NMR spectra; References to other known compounds (PDF) Complete contact information is available at: https://pubs.acs.org/10.1021/acs.joc.2c02614

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
The authors are appreciative of the financial support provided by the Faculty Senate and the Department of Chemistry and Biochemistry at the University of California, Santa Barbara. Figure 2 (nonworking examples) is dedicated to the chemical principles exemplified by late Professor Tomás Hudlicky, the undergraduate research advisor of T. Pettus. 23